There is a voluminous literature which describes the use of mAbs in the treatment of cancer, including antibodies against B-cell malignancies as described in U.S. Pat. Nos. 4,987,084 and 6,183,744, the disclosures of which are incorporated herein. These anti-cancer mAbs function by binding specifically to a tumor or circulating cancer cell, and after binding the mAb, killing the cancer cell by one or more mechanisms. These mechanisms can include complement-mediated cytotoxicity (CMC) or opsonization; antibody-dependent cell mediated cytotoxicity (ADCC); induction of programmed cell death (Apoptosis); interference with a particular cell function by blocking a receptor or upregulating/downregulating a particular signaling process. Many mAb based therapies have failed because the mAbs did not facilitate one or more of these functions efficiently.
With respect to complement activation, it is now well-recognized that one of the mechanisms by which cancer cells evade complement-mediated lysis or opsonization is by upregulating normal complement control proteins. In particular, CD46, CD55, and CD59 may be expressed at increased levels on cancer cells (compared to normal cells) and thus they are not killed by complement activation. However, there is yet another reason why a mAb may not be able to induce ADCC or opsonization of a tumor or cancer cell. Quite often complement levels are substantially reduced in cancer patients due to their disease. More particularly, one or more components of the complement cascade may be sufficiently reduced so that the mechanisms by which the mAb uses complement to facilitate cell killing (opsonization or direct lysis (CMC)) may not work effectively.
Currently there are several monoclonal antibodies (mAbs) that are being used to treat cancer including RITUXIMAB (Idec, chimeric), B1(Coulter mouse IgG2a), PANOREX (Glaxo IgG2a), C225 (Imclone chimeric IgG), VITAXIN (Medimmune chimeric IgG), Smart M195 and 1D10 (PDL humanized IgG mAbs) and CAMPATH (Berlex humanized IgG1). In particular, one of these mAbs, RITUXIMAB, has been FDA-approved for the treatment of Non-Hodgkin's Lymphoma. The mechanism used by these antibodies to effect cancer cell death is currently subject to debate. Specifically, a number of investigators contend that RITUXIMAB kills via non-complement mechanisms including Apoptosis, and Fc receptor mediated phagocytosis. However, the present invention is based in part on applicants' belief that both mAbs RITUXIMAB and CAMPATH mediate cell killing predominantly through complement activation. Since the role of complement in the mechanism of action of RITUXIMAB is still being debated, the importance of measuring complement and supplementing its levels in patients being administered therapeutic antibodies has not been previously considered. Applicants' own work (see Example 1) strongly suggests that the only important mechanism by which RITUXIMAB mediates killing of cancer cells is through complement.
It has been reported that treatment of patients with RITUXIMAB for Non-Hodgkin's Lymphoma and other B Cell lymphomas typically gives a response rate of 50%. Experiments conducted in applicants' laboratory-indicate that the active form of RITUXIMAB (RTX) in vivo is RTX covalently associated with C3b(i). It is believed that C3b(i) bound to RTX or other therapeutic mAbs provides a platform targeting epitope. If RITUXIMAB's mechanism of action requires robust complement activation, then the reduced levels of complement proteins that are often observed in cancer patients may be the cause of many of the patients' failure to respond to RITUXIMAB therapy. Furthermore, even if a patient initially has an adequate supply of complement, if that patient's tumor burden is substantial, treating with large amounts of a mAb whose mechanism of action requires complement activation may result in the available complement being used up or substantially depleted. Moreover, megadosing with additional mAb will not resolve the underlying problem relating to the lack of available complement and will not increase the effectiveness of the treatment.
The effectiveness of RTX, and other therapeutic mAbs, can be enhanced, however, if complement is restored with fresh plasma, or with individual components of the complement system (either purified natural components or recombinantly produced complement components). The improvement relates to identifying patients that will be refractory for anti-cancer passive immunotherapy due to inadequate levels of complement activity, and enhancing the efficacy of such therapy by providing a supplemental source of complement proteins.